Dysplastic nevi: difficulties in diagnosis

Dysplastic nevi (DN) are graded by their degree of atypia into 3 categories of mild, moderate, and severe. In many practices, DN with moderate or severe atypia are generally excised regardless of the status of the shave specimen margins. With a new approach toward the margins on the shave removal specimens (SRS), the goal herein is to assess whether the shave removal procedure can sufficiently remove DN with moderate or severe atypia. A total of 426 SRS diagnosed with DN showing moderate or severe atypia between January and December 2015 along with their post-shave excision specimens were reviewed. Based on the author's experience, clear or negative margins on the SRS were defined as neoplastic melanocytes confined within >0.2 mm of the lateral and deep specimen margins. The biopsy specimens were accompanied by Melan-A highlighting the subtle neoplastic cells. With a negative predictive value (NPV) of 98.4% (confidence interval: 97.2% to 100%, P < .001), DN showing moderate or severe atypia with clear margins are most likely removed by the shave procedure. Routine excision of DN showing moderate or severe atypia with clear margins on SRS is not necessary. Regular surveillance is sufficient.

STAT3 as a Biomarker of Progression in Atypical Nevi of Patients with Melanoma: Dose–Response Effects of Systemic IFNα Therapy

Histological criteria for grading of atypia in melanocytic conjunctival lesions

A total of 73 colonic adenomas, 20 with mild atypia, 26 with moderate atypia and 27 with focal carcinoma (severe atypia), were examined by complete serial section in order to find the distribution of various degrees of atypia in adenomas. In serial sections minute carcinomatous foci were found in 3 (15%) and 12 (46.2%) of the adenomas with mild and moderate atypia, respectively. Fourteen adenomas (51.9%) with focal carcinoma had multiple foci of minute carcinoma elsewhere. Adenomas less than 1 cm in diameter showed 27% malignancy rate in serial sections. From this observation it is postulated that the malignant potential of colonic adenomas is much higher than previously believed.

There is increasing evidence that melanocytic nevi with architectural and/or cytologic atypia (dysplastic melanocytic nevi [DMN]) are lesions intermediate between banal nevi and malignant melanoma. Other studies have shown conflicting results regarding the DNA content in DMN. In the present investigation, the authors measured DNA ploidy by image analysis (CAS-200 system, Cell Analysis Systems, Inc., Elmhurst, IL) using Feulgen staining in 54 melanocytic lesions. The lesions were categorized into 7 groups: compound nevus (CN) = 7; compound nevi with features of DMN (F) = 10; DMN with slight atypia = 8; DMN with moderate atypia = 9; DMN with severe atypia (S) = 8; melanoma in situ = 5; and malignant melanoma (CMM) = 7. The age distribution for these various lesions was also recorded. DNA histograms obtained by image analysis from these groups were examined for DNA aneuploidy by DNA index and classified according to Auer classifications (Auer I-IV). There was a progression of mean age for each group of melanocytic lesions, ranging from 39 years for ordinary nevi to 53 years for invasive melanoma. The Type I histogram, which is distinctly diploid, was seen in 4 of 7 cases of CN, 5 of 10 of nevi with features of dysplastic nevus, and 3 of 8 nevi with slight atypia. The Type I histogram was not observed at all in nevi with moderate atypia, severe atypia, melanoma in situ, and invasive melanoma. The Type IV histogram (aneuploid) was not identified in low grade lesions (CN, F, S), but was observed in two of nine nevi with moderate atypia, six of eight lesions with severe atypia, two of five melanomas in situ, and five of six invasive melanomas. Aneuploidy by DNA index was noted in one nevus with features of DMN, one DMN with slight atypia, one with moderate atypia, four of eight DMN with severe atypia, two of five in situ melanomas, and two of six invasive melanomas. The results show that DMN exhibit a spectrum of abnormal DNA content intermediate between banal nevi and CMM and that DNA content generally correlates with the age of patients and degree of atypia in melanocytic nevi.

The sequence of cytomorphological and cytochemical changes during 20-methylcholanthrene (20-MC)-induced malignant transformation of the bronchial epithelium was studied in six beagle dogs. The data show that submucosal injection of 20-MC in the bronchus results in the occurrence of metaplastic cells without atypia, metaplastic cells with mild, moderate, and severe atypia, and finally in cancer cells. In two control dogs treated with submucosal water injections squamous metaplastic cells without atypia, with mild, and occasionally with moderate atypia could be demonstrated. In individual morphologically classified cells quantitative cytochemical determinations of DNA and nuclear proteins were performed. In both groups of dogs squamous metaplastic cells without atypia, or with mild atypia, showed cytochemical changes similar to those found in growth-activated normal cells. In contrast, cells from 20-MC treated dogs morphologically classified as squamous metaplastic cells with severe atypia or cancer cells all showed highly increased and scattered amounts of nuclear proteins and DNA significantly deviating from those in normal proliferating cells.

Histopathological assessment of melanoma and other melanocytic skin lesions can be difficult and can vary between pathologists. Histopathological slides of 196 melanocytic skin lesions from 2009 and 2018-2019 were obtained from the archive of the Department of Pathology at Oslo University Hospital and classified into six diagnostic categories: 1) benign nevus, 2) irregular/dysplastic nevus, i.e. dysplastic nevus with moderate atypia, 3) nevus with severe atypia, i.e. dysplastic nevus with severe atypia, 4) melanoma in situ, 5) superficial spreading or lentiginous melanoma and 6) nodular melanoma. The slides were then examined independently and blindly by three experienced pathologists and categorised in the same way. Interobserver agreement was assessed with Cohen's kappa, and agreement with the original diagnosis was assessed by the proportion of assessments in the same diagnostic category. The kappa values for the assessments from the three pathologists ranged from 0.45 to 0.50. The proportion of reassessments in agreement with the original diagnostic category was 85.7% (95% CI 75.7 to 92.1), 29.2% (19.9 to 40.5), 27.8% (20.9 to 36.0), 78.3% (70.4 to 84.5), 81.2% (73.7 to 86.9) and 93.3% (82.1 to 97.7), respectively, i.e. highest for nodular melanoma. The proportion of reassessments in which the diagnosis was more serious or less serious than the original diagnosis was higher and lower, respectively, for slides from 2009 than for slides from 2018-2019. The differences between the pathologists' assessments and deviations from the original diagnoses can be explained by poorly reproducible diagnostic criteria, diagnostic entities with overlapping morphology and increasing awareness of early signs of malignancy. Some evolution in diagnostic practice cannot be ruled out.

As epithelioid cellular morphology can be seen in clinically benign usual angiomyolipomas (AMLs), we divide epithelioid AMLs into those without and with atypia, the latter category associated in the literature with malignant potential. We herein report the histologic spectrum and biologic behavior of 40 consecutive cases of epithelioid AML with atypia and assess whether cases can be stratified prognostically based on clinical and pathologic features. Atypical epithelioid cells were defined as atypical polygonal cells with abundant cytoplasm, vesicular nuclei, prominent nucleoli, and nuclear size that exceeds x2 the size of adjacent nuclei. The degree of atypia was divided to moderate and severe. Cases with bland epithelioid cells with minimal variation in nuclear size were not included. Mean age was 50.5 years (range 17 to 81), and the female to male ratio was 1.6:1. Average tumor size was 7.2 cm (range 1.0 to 17.7). The percentage of epithelioid component ranged from 5%-100% (mean 68%). Of the epithelioid component, the percentage of cells exhibiting nuclear atypia ranged in individual cases from 5% to 100% (mean of 58.4% atypical cells); 26/40 (65%) cases showed severe nuclear atypia. Cells displaying severe nuclear atypia were typically of large size with abundant cytoplasm, compared with those with moderate atypia being of small to intermediate in size with scant to moderate amount of cytoplasm. Neoplastic multinucleated giant cells and necrosis was present in 22 cases (55%) and 15 cases (37.5%), respectively. Mitoses were identified in 72.5% (29/40) of cases and ranged from 1 to 6 per 10 hpf with 7 cases showing atypical mitotic figures. Lymphovascular invasion or renal vein invasion was present in 3 cases each. Hilar and perinephric fat involvement was present in 5 and 6 cases, respectively. Clinical follow-up was available in 34 out of the 40 cases. Of the 34 cases, 9 (26%) were malignant and showed local recurrence or distant metastases. Of the 9 patients with malignant tumors, 4 died of the disease at 6, 12, 15, and 34 months after the original diagnosis was rendered, and 4 were alive with disease (mean follow-up period of 52 mo, range 24 to 72 mo). Twenty-four patients showed no evidence of recurrence and/or metastases with a mean follow-up period of 34 months (range 1 to 156 mo). We compared the 21 cases of atypical epithelioid AMLs that exhibited a benign clinical course with a minimum follow-up period of 6 months postsurgery to the 9 cases with malignant behavior. All of these were more frequently observed in clinically malignant cases: older age, larger tumor size, higher percentage of epithelioid component, severe atypia, higher percentage of atypical cells, higher mitotic count, atypical mitotic figures, necrosis, lymphovascular invasion, and renal vein invasion. Using these features, we developed a predictive model of 4 atypical features that included: (1) > or =70% atypical epithelioid cells, (2) > or =2 mitotic figures per 10 hpf, (3) atypical mitotic figures, and (4) necrosis; the presence of 3 or all of the features was highly predictive of malignant behavior. This model accurately categorized 78% of clinically malignant and 100% of the clinically benign epithelioid AMLs with atypia.

Influence of cold ischemia time on outcome of human liver transplantation using UW solution

Autoradiographic patterns of [3H]thymidine incorporation, nuclear/cytoplasmic ratios (N/C), and the percentage of dark epithelial cells were analyzed in a group of epithelial lesions induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rat tracheal transplants. It was found that similar lesions of different age exhibit the same labeling indices (LIs), therefore the lesions of different age were subsequently pooled in the following groups and studied by high resolution light microscopic autoradiography: squamous metaplasia without or with only mild atypia, squamous metaplasia with moderate atypia, squamous metaplasia with severe atypia, carcinoma in situ, and microinvasive carcinoma. Normal tracheal and esophageal epithelia were also analyzed. Whereas the normal tracheal basal layer exhibited an LI smaller than 1%, a clear difference between the carcinomas (in situ and invasive) on one hand (LI approximately 32%) and all the remaining epithelia on the other hand (LI approximately 18%) was detected. The LIs of the suprabasal cells exhibited a statistically significant difference between the squamous epithelia without atypia (LI approximately 2%) and the group comprising all the atypical lesions (LI approximately 9%). Gradients of increasing N/C (nucleus-cytoplasm ratios) values could be observed as the lesions increased in severity, especially in the middle and surface layers (e.g., in the surface layer regular metaplasia N/C = 0.08, squamous metaplasia with moderate atypia N/C = 0.26, and carcinoma in situ N/C = 0.50). Dark cells were absent in the normal esophageal epithelium, were present in moderate numbers in the basal layer of regular squamous metaplasia (18%), and increased markedly in the atypical epithelial lesions (approximately 50% in the atypical squamous metaplasias and 70% in carcinoma in situ). In the suprabasal layer dark cells increased from 3% in squamous metaplasia with moderate atypia to 28% in metaplasia with severe atypia and 56% in carcinoma in situ. The results confirm in a quantitative fashion that disturbances of cell maturation and cell proliferation are key features of dysplastic lesions induced by chemical carcinogens, and suggest the use of objective parameters for evaluation and classification of preneoplastic alterations.

We used computerized image analysis cytometry to analyze 10 melanocytic lesions from each of the following categories: common acquired nevi, melanocytic nevi with architectural features of dysplasia, dysplastic melanocytic nevi (DMN) with slight atypia, DMN with moderate atypia, DMN with severe atypia, and superficial spreading melanomas. The nuclei of at least 50 consecutive nevomelanocytes in the most atypical zones were digitized at x 1000 under oil immersion, without knowledge of diagnosis by one observer. Grading of atypia was based on current practices as described in the literature. The results showed significant differences (p < 0.05) in nuclear area and standard deviation of nuclear area between melanoma and DMN with severe atypia, and between DMN with severe atypia and all other categories of nevi. There were no differences among any lesions with respect to nuclear shape. No differences in nuclear area were found among DMN with moderate, or slight atypia, nevi with features of dysplasia, and typical nevi. These results show for the first time objective distinction of low-grade (slight-moderate atypia), and high-grade or severe atypia in pre-malignant nevomelanocytic lesions of the skin.

Minute flat depressed neoplastic lesions of the colon detected by contrast chromoscopy using an indigo carmine capsule

Clarification of the ultrastructural features of the three different grades of histologic atypia of adenomas (i.e., mild, moderate, and severe atypia) with reference to carcinoma of the human colon and rectum was undertaken using electron microscopic quantitative analysis. Ten normal epithelia, 36 adenomas (14 with mild atypia, 13 with moderate atypia, and 9 with severe atypia) and 14 carcinomas (well-differentiated adenocarcinoma) were examined with light and electron microscopes. Although it has been generally accepted that malignant transformation of an adenoma gradually proceeds with increasing atypia, using light microscopy, ultrastructural quantitative analysis clearly revealed that fine features of individual atypia did not correspond with histologic grades of atypia. Ultrastructural changes occurred abruptly in moderate atypia and showed similar cellular characteristics to carcinoma cells. Mild atypia was almost similar in appearance to normal epithelial cells. Striking changes in the moderate atypic cells were plane apposition of the cell membrane, decrease of the desmosomes, and increase of the lysosomes. These atypical cells were assumed to play a significant role in the adenoma-carcinoma sequence. Therefore, radical surgical therapy would be required for moderate atypic adenoma of the large bowel that is difficult to remove endoscopically.

Cytology is an essential tool for the investigation of urinary tract malignancy. In this audit, we aimed to assess our laboratory performance in the diagnosis of upper urinary tract malignancy and to use the information provided to improve our service. We retrieved cytology reports of upper urinary tract specimens from two periods, re-evaluated the cases, compared the reports with histology data and estimated the sensitivity, specificity and positive predictive value (PPV). In the time interval between the two periods, we adopted new terminology, established better communication with clinicians and gained experience in the field. Finally, the data from the two periods were compared. In phase A, we estimated a sensitivity of 73%, specificity of 86% and PPV of 84.6%. As a result of the cytological re-evaluation, correlation with histology and clinical follow-up, plus communication with the clinicians during the audit, we established new terminology and a new request form. A three tiered grading system of atypia (mild, moderate and severe) was replaced by a two tiered grading system. The first category "atypia probably benign" corresponded to "mild atypia" while the second category "atypia, not otherwise specified" corresponded to "moderate atypia". The cases diagnosed as "severe atypia" were reclassified as "suspicious for malignancy". In phase B, the sensitivity, specificity and PPV were 75%, 89% and 90%, respectively. Our laboratory performance is in concordance with reported data and has been improved through this study. The audit process is extremely valuable for the identification of problems, for taking action and, finally, for the improvement of the clinical cytology service in the field of upper urinary tract malignancy.

Objective We previously surveyed cyclin D1 expression in common acquired nevi, Spitz nevi, and malignant melanomas and reported that benign nevi maintain a zonal pattern of cyclin D1 expression, in contrast with malignant melanomas. Our aim was to extend those observations by examining cyclin D1 expression in dysplastic nevi. Methods Cyclin D1 overexpression in 23 dysplastic nevi was detected by an immunohistochemical technique. The extent of atypia of the nevi was graded as mild, moderate, or severe, using previously established criteria. Results Cyclin D1 overexpression in dysplastic nevi maintained a zonal pattern, similar to Spitz nevi. Cyclin D1 overexpression was greatest in the region of the epidermal-dermal junction and was significantly less prominent in the papillary and reticular dermis, suggesting that cyclin D1 expression is under cell control and correlates with maturation of nevus cells. Cyclin D1 overexpression also correlated with cytologic atypia, as dysplastic nevi with moderate or severe cytologic atypia contained a greater percentage of cyclin D1-positive cells than did nevi with mild atypia. Six dysplastic nevi with many cyclin D1--positive cells were assessed by fluorescence in situ hybridization studies using cyclin D1--specific and chromosome 11 centromeric probes. In all cases, there was no evidence of 11q13 translocation, amplification, or trisomy of chromosome 11. Conclusions Cyclin D1 may be involved in the pathogenesis of dysplastic nevi. Cyclin D1 overexpression does not appear to be explained by cyclin D1 locus amplification or translocation in most cases, and it may be a result of other cell abnormalities that up-regulate the protein level of cyclin D1.